Domperidone, 5-chloro-1-[1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]piperidine-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, is a weak base (pKa=7.89) practically insoluble in water and with a lipid to water ratio (log P) of 3.90. It is a potent peripheral dopamine2 antagonist that exerts its gastrokinetic action by acting on the peripheral dopamine2 receptors in the stomach and is a unique compound with both gastrokinetic and antiemetic activity. Unlike metoclopramide, another dopamine-receptor antagonist, domperidone does not readily cross the blood-brain barrie, therefore it has rather minimal extrapyramidal side effects. Clinically, domperidone has been shown to be useful in the treatment of various gastric motility disorders, namely chronic and subacute gastritis, to prevent GI symptoms associated with the use of dopamine agonists in Parkinson's disease, in diabetic gastroparesis, in anorexia nervosa and in patients with postvagotomy gastroparesis.
Therapeutically active compounds are frequently administered to patients in the form of a tablet when the drug is intended for oral administration, since tablets are an especially convenient pharmaceutical form for manufacture, storage and general usage. However, problems may arise with the administration of such tablets to patients who have difficulty in swallowing, for example children, elderly people or more seriously ill patients, especially if the tablets are large in size. Suspension dosage forms could solve this problem, but they have other drawbacks: they have to be reconstituted prior to administration and, sometimes, stored under refrigerated conditions to prevent them from deterioration. Suspensions are also inconvenient to carry while travelling and also involve the risk of inaccurate measurement and dosing. Freeze drying processes have been used to prepare fast disintegrating dosage forms. Depending on the manufacturing process, the product obtained is characterised by a highly porous microstructure of the soluble supporting agent in which the active ingredient is homogeneously dispersed. Although this technology originates a product which rapidly disintegrates in water or in the oral cavity, a drawback is represented by the poor physical integrity of its physical structure, which severely limits further manufacturing operations such as forming blister packs. Another significant drawback of the freeze drying technology is the high production cost, due to the long freeze drying cycles and the complexity and specificity of industrial plants, important factors which prejudice the large scale use of this technology for the development of rapid disintegrating tablets.
Another type of water-dispersible tablets includes effervescent formulations which rely on the formation of a gas to quickly break up the tablet, but these also involve expensive manufacturing methods and strict regulations for such manufacture.
There is a need for dosage forms which would have the convenience of administration of the suspensions and all the advantages of the tablets and capsule formulations. A dispersible tablet is one dosage form that meets these needs. They are easy to carry and can be accurately a conveniently reconstituted in water or aqueous medium immediately before its administration to patients, thus avoiding the need to store solutions or dispersions with risk of hydrolysis. The patient should easily drink the obtained dispersion.
Rapidly disintegrating tablets are known from EP 0 211 946 or WO 8604817, which describe a controlled release potassium chloride tablet that comprises potassium chloride crystals having a mesh size of about 30 to about 50 mesh which are coated with ethylcellulose and hydroxypropylcellulose. The tablets disintegrate rapidly in an aqueous environment, however these tablets contain microparticles that when ingested are perceived as individual grains in the mouth in an unpleasant manner.
EP 0 685 231, U.S. Pat. Nos. 4,886,669 and 5,698,226 patents, describes water-dispersible tablets containing lamotrigine and 0.25 to 40% w/w of a pharmaceutically acceptable swellable clay which is present within the granules of a tablet. However, the use of swellable clays cans undesirable retard the disintegration time of the tablet.
EP 1 058 538 refers to fast disintegrating tablets comprising a drug in multiparticulate form, one or more water insoluble inorganic excipients, one or more disintegrating agents and, optionally, one or more substantially water soluble excipients, the amount of said ingredients being such as to provide a disintegration time for the tablet in the order of 75 seconds or less, typically 30 seconds or less. The water-soluble components are in the range of 0-25% of the total formulation by weight, most preferably about 4-16% by weight. The substantially water insoluble inorganic filler is dibasic calcium phosphate, hydrated or anhydrous.
EP 1 156 786 concerns to fast disintegrating tablets such as those designed to dissolve in the mouth in contact with saliva in less than 30 seconds forming a easy-to-swallow suspension and based on an active substance in the form of coated microcrystals or microgranules and a mixture of carriers comprising at least a disintegrating agent, a soluble agent and a lubricant agent.
EP 1 331 001 patent describes new galenic dispersible and soluble paracetamol formulations comprising a mixture of paracetamol and citric acid in a proportion of 85:15 to 90:10 w/w among other pharmaceutically acceptable components, in an exsiccation state corresponding to a water percentage of less than 0.6% and it is in the form of powder, granulate or tablet.
EP19990941105 application refers to a dosage form that rapidly disintegrates in the mouth and forms viscous slurry of either microcapsules or a powder.
EP19970927372 application refers to intraorally rapidly disintegrable tablet comprising a sugar alcohol or saccharide having an average particle diameter of not more than 30 μm, an active ingredient and a disintegrating agent.
EP19990954046 application concerns an improved multiparticulate tablet disintegrating in the mouth in contact with saliva in less than 40 seconds, characterised by particles of coated active principle, said particles having intrinsic compression properties, and by a mixture of carriers being the proportion of carriers mixture relative to coated active principle particles 0.4 to 0.6 parts by weight.
EP20000113571 application discloses a flash-melt pharmaceutical dosage form comprising a medicament and a combination of four excipients consisting of a superdisintegrant, a dispersing agent, a distributing agent and a binder. The four excipients may be dry granulated with the active ingredient and suitable conventional ingredients.
EP20010904162 application refers to a water-dispersible formulation of paroxetine for immediate oral administration that comprises a dry blend of paroxetine, a water-soluble dispersing agent selected from polyvinyl pyrrolidone, calcium carbonate and sodium starch glycolate, and a taste-masking agent, selected from potassium form polyacrylic acid ion exchange resins, β-cyclodextrin, lecithin and methacrylic acid copolymers, presented as a dispersible powder or moulded into a tablet.
EP20020727563 application relates to fast disintegrating tablets obtained by direct compression comprising meloxicam or a pharmaceutical acceptable salt thereof, containing 20-50% (w/w) of starch and free of cellulose.
EP20030764046 application relates to a process for the preparation of a dispersible tablet dosage form comprising β-lactam antibiotics for oral administration and a disintegrating agent being used both intragranularly and extragranularly.
EP20030706747 application relates to fast disintegrating tablets comprising an active ingredient and one or more disintegrating agents characterised in that the tablets comprise agglomerates having agglomerated particles of at least 50 βm, said agglomerates comprising at least 10% by weight of a superdisintegrating agent selected from croscarmellose cellulose, crospovidone and sodium starch glycolate and being free of active ingredient.
EP20030769384 application relates to dispersible tablets comprising deferacirox or pharmaceutically acceptable salts thereof in an amount of from 5 to 40% in weight by weight of the total tablet and comprising at least one filler in a total amount of about 35 to 55%, at least one disintegrating agent in a total amount of about 10 to 35%, at least one binder in a total amount of 1.5 to 5%, at least one surfactant in a total amount of about 0.2 to 1%, at least one glidant in a total amount of about 0.1 to 0.5% and at least one lubricant in a total amount of less than about 0.4% in weight, all of them expressed in relation of the total weight of the tablet.
EP20030784317 application relates to dispersible tablets of cephalexin comprising granulation of cephalexin with disintegrating agent and colloidal silicon dioxide and binder solution to form granules, drying and mixture of the granules with disintegrating agents, fillers, lubricants and, optionally, other excipients.
WO2004/000281 application relates to rapidly disintegrating tablets intended to be used as orodispersible tablets or dispersible tablets. They are ingested either by dispersing directly in the mouth or in water and contain silicified microcrystalline cellulose.
There are several formulations for good-disintegrating tablets, but said tablets have several disadvantages. Normally those tablets have high percentages of disintegrating agents and are very porous, thus very sensitive to humidity. Moreover, the presence of such ingredients tends to weaken the tablet's structure, leading to high friability and low hardness values. The aim of the present invention is to avoid the above-mentioned inconvenient and provide a fast water-dispersible tablet comprising domperidone to provide a dispersion which will pass through a 710 μm diameter mesh size sieve, which is capable of dispersing in water within 3 minutes, preferably within 2 minutes and most preferably 1 minute, having an enhanced structural integrity, for instance having a friability lower than 1.0%, with a pleasant taste and the absence of perceptible granules in the mouth. The present invention also discloses the process to obtain the above-mentioned formulations.
None of the prior art describes fast water-dispersible tablets containing domperidone.